Investigating sex-specific associations of lipid traits with type 2 diabetes, glycemic traits and sex hormones using Mendelian randomization

Background Low-density lipoprotein (LDL)-cholesterol is positively associated with cardiovascular disease (CVD) and inversely associated with type 2 diabetes, which could detract from lipid modification. Here, we examined whether lipid traits potentially relevant to CVD aetiology, i.e. apolipoprotein B (apoB), triglycerides (TG) and lipoprotein(a) [Lp(a)] exhibited the same associations. We investigated sex-specifically, including the role of sex hormones, because sex disparities exist in lipid profile and type 2 diabetes. We also replicated where possible. Methods We used Mendelian randomization (MR) to examine sex-specific associations of apoB, TG and Lp(a) with type 2 diabetes, HbA1c, fasting insulin, fasting glucose, testosterone and estradiol in the largest relevant sex-specific genome-wide association studies (GWAS) in people of European ancestry and replicated where possible. We also assessed sex-specific associations of liability to type 2 diabetes with apoB, TG and Lp(a). Results Genetically predicted apoB and Lp(a) had little association with type 2 diabetes or glycemic traits in women or men. Genetically predicted higher TG was associated with higher type 2 diabetes risk [odds ratio (OR) 1.44 per standard deviation (SD), 95% confidence interval (CI) 1.26 to 1.65], HbA1c and fasting insulin specifically in women. Higher TG was associated with lower testosterone in women and higher testosterone in men, but with lower estradiol in men and women. Genetic liability to type 2 diabetes was associated with higher TG in women, and possibly with lower apoB in men. Conclusions Lipid traits potentially relevant to CVD aetiology do not exhibit contrasting associations with CVD and type 2 diabetes. However, higher TG is associated with higher type 2 diabetes risk and glycemic traits, which in turn further increases TG specifically in women, possibly driven by sex hormones. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-022-01714-2.

b. Estimates are expressed in standard deviation for lipid fractions, and in odds ratio for coronary artery disease.
Additional file 1: Table S2. Odds ratio or mean difference in z-score that was detectable at 80% power (α=0.05) for each analysis. Additional file 1: Table S3. Mendelian randomization estimates for ancestry -and sex-specific associations of genetically predicted triglycerides (instrumented by the SNPs from GLGC excluding the UK Biobank participants) with type 2 diabetes, glycemic traits and sex hormones. b. Estimates are expressed in standard deviation for triglycerides, HbA1c and testosterone, in odds ratio for type 2 diabetes, in pmol/L (natural log transformed) for fasting insulin, in mmol/L for fasting glucose, and in log odds ratio (above and below the limit of detection) for estradiol.
Additional file 1: Table S4. Mendelian randomization estimates for ancestry -and sex-specific associations of genetically predicted lipid traits (instrumented by the SNPs from the UK Biobank) with type 2 diabetes (including SNPs explaining more of the variance in the outcome than in the exposure). b. MVMR1 includes apoB, TG and Lp(a); MVMR2 includes apoB, TG, Lp(a) and body mass index.
c. Estimates are expressed in standard deviation for lipid fractions, and in odds ratio for type 2 diabetes.
Additional file 1: Table S5. Mendelian randomization estimates for sex -specific associations of genetically predicted lipid traits (instrumented by the SNPs from the UK Biobank) with glycemic traits in people of European ancestry (including SNPs explaining more of the variance in the outcome than in the exposure). c. Estimates are expressed in standard deviation for lipid fractions and HbA1c, in pmol/L (natural log transformed) for fasting insulin, and in mmol/L for fasting glucose.

Sex
Additional file 1: Table S6. . Mendelian randomization estimates for ancestry-and sex-specific associations of genetically predicted lipid traits (instrumented by the SNPs from the UK Biobank) with type 2 diabetes (excluding SNPs explaining more of the variance in the outcome than in the exposure). b. MVMR1 includes apoB, TG and Lp(a); MVMR2 includes apoB, TG, Lp(a) and body mass index.
c. The SNPs explaining more of the variance in the outcome than in the exposure identified by Steiger filtering are rs1800562, rs597808 and rs7140110 for apoB on HbA1c in women, rs2519093, rs6602911 and rs80215559 for apoB on HbA1c in men, rs10440833, rs12486657, rs2519093, rs7140110 and rs76895963 for TG on HbA1c in women, and rs76895963 for TG on HbA1c in men.
d. Estimates are expressed in standard deviation for lipid fractions and HbA1c, in pmol/L (natural log transformed) for fasting insulin, and in mmol/L for fasting glucose.
Additional file 1: Table S8. 8. Mendelian randomization estimates for sex-specific associations of genetically predicted lipid traits (instrumented by the SNPs from the UK Biobank) with sex hormones in people of European ancestry (including SNPs explaining more of the variance in the outcome than in the exposure). c. Estimates are expressed in standard deviation for lipid fractions and testosterone, and in log odds ratio (above and below the limit of detection) for estradiol.
Additional file 1: Table S9. Mendelian randomization estimates for sex -specific associations of genetically predicted lipid traits (instrumented by the SNPs from the UK Biobank) with sex hormones in people of European ancestry (excluding SNPs explaining more of the variance in the outcome than in the exposure). b. MVMR1 includes apoB, TG and Lp(a); MVMR2 includes apoB, TG, Lp(a) and body mass index.

Sex
c. The SNPs explaining more of the variance in the outcome than in the exposure identified by Steiger filtering are rs13247874 for apoB on testosterone in women, and rs7199293 for TG on testosterone in women.
d. Estimates are expressed in standard deviation for lipid fractions and testosterone, and in log odds ratio (above and below the limit of detection) for estradiol.